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(Circulation. 1997;96:922-926.)
© 1997 American Heart Association, Inc.

Articles

Increase in Angiotensin II Type 1 Receptor Expression Immediately After Ischemia-Reperfusion in Isolated Rat Hearts

B. C. Yang, MD, PhD; M. I. Phillips, PhD; P. E. J. Ambuehl, PhD; L. P. Shen, BS; P. Mehta, MD; ; J. L. Mehta, MD, PhD

From the Departments of Medicine, Pediatrics, and Physiology, University of Florida and VA Medical Center, Gainesville.

Correspondence to J.L. Mehta, MD, PhD, Department of Medicine, University of Florida College of Medicine, 1600 Archer Rd, PO Box 100277 JHMHC, Gainesville, FL 32610. E-mail mehta.medcs0{at}shands.ufl.edu

	Abstract

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Background Myocardial ischemia is known to upregulate the systemic renin-angiotensin system, which influences myocardial ischemic events by affecting hemodynamics and hemostatic activity. This study was designed to examine whether angiotensin II (Ang II) receptor expression in the myocardium is altered immediately after ischemia-reperfusion.

Methods and Results Isolated buffer-perfused Sprague-Dawley rat hearts were subjected to continuous perfusion (control, n=5) or to 25 minutes of global ischemia followed by 30 minutes of reperfusion (n=10). Autoradiographic analysis for Ang II receptors of multiple myocardial sections was performed. Whereas continuous perfusion of hearts resulted in minor changes in coronary perfusion pressure (CPP), left ventricular end-diastolic pressure (LVEDP), and developed left ventricular pressure (dLVP=LVSP-LVEDP), ischemia-reperfusion caused a marked increase in CPP and LVEDP and a decrease in dLVP, indicating severe cardiac dysfunction. Concurrently, total myocardial Ang II receptor expression was greater (P<.05) in hearts subjected to ischemia-reperfusion than in the continuously perfused control hearts. Most of the increase in Ang II receptor expression was due to an increase in type 1 receptor (AT₁) expression (34.6±6.5 versus 18.2±4.4 fmol/g, P<.05), because Ang II type 2 receptor expression was unaffected. To examine the importance of AT₁ receptor expression, another group of isolated rat hearts (n=5) was perfused with buffer containing losartan (10^-5 mol/L) and subjected to ischemia followed by reperfusion. Perfusion of hearts with losartan attenuated the ischemia-reperfusion–induced cardiac dysfunction. Perfusion of hearts with losartan also blocked the ischemia-reperfusion–induced increase in myocardial AT₁ binding.

Conclusions These observations indicate that myocardial AT₁ expression increases immediately after ischemia-reperfusion and contributes to cardiac dysfunction.

Key Words: angiotensin • ischemia • reperfusion • myocardium

	Introduction

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The renin-angiotensin system is an important factor in the pathophysiology of ischemic coronary events.^{1 2 3 4 5 6} A deletion polymorphism in the ACE gene, which is associated with a high serum level of ACE, has been reported to be related to high risk of myocardial infarction and sudden death.^{1 2 3 4} Plasma renin activity also predicts acute myocardial infarction in patients with hypertension, irrespective of serum cholesterol levels. Ang II contributes to the evolution of ischemic coronary events through its hemodynamic effects.⁷ Ang II may also contribute in the short term to ischemic events by affecting hemostatic activity.^{8 9} In humans⁸ and in cultured cells,⁹ Ang II has been observed to stimulate the synthesis of plasminogen activator inhibitor-1 and thereby promote thrombosis. Both ACE inhibitor and Ang II receptor antagonists have been shown to protect myocardium from ischemia-reperfusion injury in experimental animal models.^{10 11} Recent clinical trials^{12 13} have also confirmed the effectiveness of ACE inhibition in preventing recurrent myocardial infarction and the progression of postinfarction left ventricular dysfunction to heart failure.

Ang II receptors include at least two different subtypes, AT₁ and AT₂.^{7 14} Both AT₁ and AT₂ receptors are expressed in rat heart and distributed in the myocardium.^{15 16 17} Sun and Weber¹⁸ showed that myocardial AT₁ receptor density is significantly increased in association with ACE expression and collagen formation at day 3 through week 8 after myocardial infarction in rats. These investigators suggested that the increased AT₁ receptor expression may relate to tissue repair or to fibrogenic response to tissue injury after ischemia. However, the status of AT₁ receptor expression soon after ischemia is not clear. The present study was designed to examine whether the increased AT₁ receptor expression plays a role in the pathophysiology of myocardial ischemia-reperfusion injury.

	Methods

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Isolated Perfused Heart Model
Male Sprague-Dawley rats weighing 200 to 225 g (heart weights, 820 to 880 mg) were anesthetized with sodium pentobarbital (50 mg/kg IP). The hearts were rapidly excised and placed in ice-cold K-H buffer (composition in mmol/L: NaCl 118, KCl 4.7, KH₂PO₄ 1.2, MgSO₄ 1.2, CaCl₂ 2.5, NaHCO₃ 25, and glucose 11; pH 7.4). Within 1 minute, the hearts were transferred to a perfusion apparatus and perfused via the aorta with oxygen-saturated (95% O₂/5% CO₂) K-H buffer kept at 37°C with a MasterFlex pump (model 7015-21, Cole-Palmer Instrument Co) according to the modified Langendorff procedure.^{19 20} The heart was placed in a semiclosed, circulating water–warmed (37°C) air chamber, paced atrially with a Medtronic 5320 pacemaker at a rate of 300 bpm, and perfused at a constant flow (5.5 to 6.0 mL/min). CPP was measured via a catheter placed just proximal to the aorta and connected to a Gould Statham P23ID pressure transducer. A latex balloon filled with water and connected to a Gould Statham P23ID pressure transducer was inserted into the left ventricle through the left atrium to measure LVEDP, LVSP, and dLVP. LVEDP at baseline during equilibration was set at 5 to 7 mm Hg. CPP, LVEDP, and LVSP were continuously recorded on a four-channel recorder (Astro-Med). Heart rate was monitored from a fast-speed tracing of the LVSP signal.

Experimental Protocol
In pilot experiments (n=8), hearts perfused with buffer alone were exposed to 40 minutes of ischemia (perfusion stopped) followed by 30 minutes of reperfusion. The LVEDP fell to zero during the first few minutes of ischemia, started to rise at 16 to 18 minutes of ischemia, reached the peak value at 23±1 minutes of ischemia, and then gradually fell again. Therefore, the ischemia time in this study was kept at 25 minutes.

Five hearts were continuously perfused with K-H buffer for 75 minutes and served as sham ischemia-reperfusion. In the ischemia-reperfusion groups, after 20 minutes of equilibration, hearts were subjected to 25 minutes of ischemia and then reperfused for 30 minutes. Rat hearts were perfused with K-H buffer alone (n=10) or K-H buffer containing the selective AT₁ receptor antagonist losartan 10^-5 mol/L (n=5). At the end of reperfusion, hearts were frozen on dry ice for Ang II receptor analysis by autoradiography.

Determination of Ang II Receptor Expression in Myocardial Sections by Autoradiography
Hearts were frozen on dry ice. Transverse sections 20 µm thick were made at -20°C. The sections were then mounted onto chrome-alum-gelatin–coated slides and incubated with 250 to 300 pmol/L ¹²⁵I-labeled Sar-Ile-Ang II for 2 hours in 10 mmol/L sodium biphosphate buffer (pH 7.2) or buffer containing 10 µmol/L of the Ang II receptor antagonist [Sar¹,Val⁵,Ala⁸]–Ang II, 10 µmol/L of the AT₁ receptor antagonist losartan, or 10 µmol/L of the AT₂ receptor antagonist PD123,177. The sections were washed in 10 mmol/L sodium biphosphate buffer (pH 7.2) and dried. Autoradiograms were generated by apposition of slide-mounted tissue sections with x-ray film (Hyperfilm-³H, Amersham) for 3 weeks. Densitometric analysis of the autoradiographs was carried out with Image Systems (MCID M1 software with Tk/M1 Turnkey System with an 80486, 33-mHz computer, Imaging Research, Inc).^{17 18 21}

Data Analysis
CPP, LVEDP, LVSP, and dLVP were expressed in mm Hg. All values are given as mean±SEM. Differences between specific means were examined by ANOVA with the Student-Newman-Keuls test. A value of P<.05 was considered statistically significant.

	Results

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Cardiac Dynamics During Ischemia-Reperfusion
The basal values of CPP, LVSP, LVEDP, and dLVP were similar in all groups of hearts.

In the control, continuously buffer-perfused hearts observed for 75 minutes, there were only minimal (5% to 10%) changes in the indices of cardiac function. In hearts perfused with buffer alone, 25 minutes of ischemia followed by 30 minutes of reperfusion resulted in a marked increase in CPP and LVEDP and a decrease in dLVP (all P<.01 versus preischemia values). A representative example of marked cardiac dysfunction after ischemia-reperfusion is shown in Fig 1, and data from multiple experiments are summarized in Fig 2.

View larger version (16K): [in this window] [in a new window]   Figure 1. Representative experiment showing marked deterioration of cardiac function after 25 minutes of global ischemia and 30 minutes of reperfusion. CPP and LVEDP increased, and LVSP fell slightly, resulting in marked decrease in dLVP.

View larger version (33K): [in this window] [in a new window]   Figure 2. Summary of data on cardiac function after ischemia and reperfusion in buffer-perfused (n=10) and losartan-perfused (n=5) hearts. Increase in CPP after ischemia-reperfusion is less in losartan-treated hearts than in buffer-perfused hearts (P<.05). LVSP in losartan-treated hearts after ischemia-reperfusion is higher than in buffer-perfused hearts. dLVP was preserved in losartan-treated group (P<.05 vs buffer-perfused group). Data points reflect mean±SEM.

Perfusion of hearts with losartan markedly attenuated the ischemia-reperfusion–induced myocardial dysfunction, indicated by relative preservation of dLVP and minimization of increase in CPP (both P<.05 versus changes in hearts perfused with K-H buffer alone). Data from multiple experiments are summarized in Fig 2.

Myocardial Ang II Receptor Expression After Ischemia-Reperfusion
Sham control hearts exhibited some total Ang II and AT₁ receptor binding and minimal levels of AT₂ receptor binding. Ischemia followed by reperfusion resulted in an immediate and significant increase in myocardial total Ang II receptor expression (P<.05 versus sham control hearts). The increase in Ang II expression was entirely due to an increase in AT₁ receptor expression (P<.05 versus sham control hearts), because AT₂ receptor expression was not affected by ischemia-reperfusion. Results of a representative experiment are shown in Fig 3. A summary of data from several experiments is shown in Fig 4.

View larger version (84K): [in this window] [in a new window]   Figure 3. Representative autoradiographs from a buffer-perfused control heart (top) and a heart subjected to 25 minutes of ischemia and 30 minutes of reperfusion. Hearts were immediately frozen and then subjected to autoradiography (see text for details). Note marked increase in total Ang II and AT1 receptor expression, while AT2 receptor expression is unchanged.

View larger version (37K): [in this window] [in a new window]   Figure 4. Summary of data on autoradiographic analysis of total Ang II, AT1, and AT2 receptor expression in control, buffer-perfused ischemia-reperfusion, and losartan-perfused ischemia-reperfusion hearts. Numbers of rats in each group were 5, 10, and 5, respectively. Data are mean±SEM.

Perfusion of the hearts with the AT₁ receptor antagonist losartan significantly attenuated the ischemia-reperfusion–increased myocardial total Ang II receptor binding and abolished the AT₁ receptor binding (Fig 4).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study demonstrates that ischemia followed by reperfusion results in cardiac dysfunction in isolated perfused rat hearts, and the cardiac dysfunction is associated with a marked increase in total Ang II receptor expression in the myocardium immediately after ischemia-reperfusion. Since AT₂ receptor expression was unchanged, the marked increase in Ang II expression could be accounted for entirely by an increase in AT₁ receptor expression.

Angiotensin is a potent coronary artery constrictor in the rat that contributes to the ischemic coronary events through its hemodynamic effects.²² All components for a tissue renin-angiotensin system, including mRNA for renin and angiotensinogen, have been demonstrated in the rat heart.^{6 23 24} On the basis of their differential pharmacological and biochemical properties, at least two distinct Ang II receptor subtypes have been defined and designated as AT₁ and AT₂.²⁵ To date, evidence from experimental animals indicates that almost all of the known effects of Ang II in adult tissues are attributable to AT₁ and that AT₂ receptor activation is related to development.^{25 26 27 28 29} Since the predominant active subtype of Ang II receptor in myocytes changes from AT₂ to AT₁ in the growing rat,^{14 17} we speculated that the activation of the AT₁ receptor must be the primary factor in response to Ang II, resulting in an increase in coronary vascular resistance during ischemia and reperfusion in the adult rat. In accordance with this hypothesis, we found a marked increase in AT₁ receptor expression immediately after ischemia without any change in AT₂ receptor expression.

Sun and Weber¹⁸ reported that (1) there is relatively low Ang II receptor expression in the normal rat myocardium; (2) Ang II receptor expression increases markedly at the site of left ventricular myocardial infarction at day 3 and weeks 1, 2, 4, and 8 after infarction; (3) Ang II receptor expression increases in the pericardial tissues after pericardiotomy; and (4) tissue Ang II receptor expression is displaced by the AT₁ receptor antagonist losartan but not by the AT₂ receptor antagonist PD123,177. These authors¹⁶ suggested that AT₁ receptor activation plays a role in mediating the fibrogenic response to tissue injury in the rat heart.

The present study is probably the first to demonstrate increased myocardial AT₁ receptor expression immediately after 25 minutes of ischemia and 30 minutes of reperfusion in the isolated buffer-perfused rat heart. The markedly increased AT₁ receptor expression after ischemia-reperfusion most likely contributes to the increase in coronary vascular resistance and cardiac dysfunction after ischemia-reperfusion.

Other investigators¹⁶ have demonstrated that Ang II receptor expression in the heart and kidney is markedly reduced after in vivo infusion of Ang II and that Ang II receptor expression in the heart and kidney is inversely related to the circulating level of Ang II in rats, which is in keeping with the phenomenon of receptor regulation. Although ischemia-reperfusion has been reported to increase the plasma level of Ang II,³⁰ the ischemia-reperfusion–induced immediate increase in myocardial AT₁ receptor expression observed in the present study cannot be a response to the changes in circulating Ang II level, because the hearts were isolated and perfused with physiological buffer. Local myocardial Ang II synthesis and secretion may be critical for the determination of cardiac function in the isolated perfused heart and may regulate myocardial Ang II receptor expression. However, we do not have data on myocardial Ang II synthesis and release in the setting of ischemia-reperfusion in the isolated rat heart. Nonetheless, increased Ang II receptor expression suggests that the ACE activity or Ang II synthesis in the myocardium may be diminished immediately after ischemia-reperfusion.

The autoradiographic technique used in this study does not permit precise localization of the Ang II receptor, ie, in myocytes, fibroblasts, or blood vessels. Feolde et al¹⁷ demonstrated that Ang II receptor sites are located on the myocardial cell membrane. If the increased AT₁ expression occurs at the myocyte level, Ang II–mediated signaling may directly affect myocyte function. If it is the vascular endothelial or smooth muscle cells that show increased AT₁ expression, the effects of Ang II–mediated signaling may increase local vasoconstriction. If fibroblasts are the predominant cell type that exhibits increased AT₁ expression, the Ang II–mediated signaling would be expected to influence tissue remodeling. The last is an unlikely event, because the increase in AT₁ receptor expression was observed immediately after ischemia-reperfusion. Further studies need to be done to define the precise localization of AT₁ receptors.

It is not known whether the increase in myocardial or vascular AT₁ receptor expression immediately after ischemia-reperfusion is due to the externalization of AT₁ receptors or to the increased AT₁ receptor synthesis. Studies on differential regulation of mRNA specific for ß-adrenergic receptor subtypes, which are rapidly downregulated in failing human hearts, indicate that the steady-state concentration of specific mRNA and the corresponding receptor densities are highly correlated.³¹ This suggests that the regulation of receptors is most likely at the mRNA level.

To examine the significance of myocardial AT₁ receptor expression in the determination of hemodynamic response, we conducted studies in which a group of isolated rat hearts was perfused with the specific AT₁ receptor blocker losartan. The blockade of AT₁ receptors was evident from autoradiographic analysis. Concurrently, losartan significantly attenuated the ischemia-reperfusion–induced changes in coronary vascular resistance and cardiac function. These observations suggest a critical role of AT₁ receptor expression in the myocardium in the determination of dynamic response to ischemia-reperfusion.

Several studies have implicated the renin-angiotensin system in the genesis of ventricular arrhythmias after ischemia and reperfusion. In experimental models, ACE inhibitors have been associated with reduction in ischemia-reperfusion–induced ventricular arrhythmias.^{32 33} ACE inhibitors have been reported to reduce cardiac arrhythmias in patients with congestive heart failure.³⁴ Angiotensin II has been indirectly shown to produce coronary constriction during ischemia.³⁵ The present study offers new insight into these effects. This study shows that reperfusion injury induces an increase in the number of Ang II receptors, specifically the AT₁ subtype.

In summary, this study shows that a brief period of ischemia followed by reperfusion in isolated rat hearts results in an immediate increase in myocardial AT₁ receptor expression. The AT₁ receptor expression appears to have an important effect on myocardial functional response to ischemia-reperfusion.

	Selected Abbreviations and Acronyms

 

Ang II = angiotensin II AT1 = Ang II type 1 receptor AT2 = Ang II type 2 receptor CPP = coronary perfusion pressure dLVP = developed left ventricular pressure (=LVSP-LVEDP) K-H = Krebs-Henseleit LVEDP = left ventricular end-diastolic pressure LVSP = left ventricular systolic pressure

	Acknowledgments

 
This study was supported by a Grant-in-Aid from the American Heart Association, Florida Affiliate, St Petersburg, and a Merit Review Award from the VA Central Office.

Received October 14, 1996; revision received January 31, 1997; accepted February 3, 1997.

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				D. Li, T. Saldeen, F. Romeo, and J. L. Mehta Oxidized LDL Upregulates Angiotensin II Type 1 Receptor Expression in Cultured Human Coronary Artery Endothelial Cells : The Potential Role of Transcription Factor NF-{kappa}B Circulation, October 17, 2000; 102(16): 1970 - 1976. [Abstract] [Full Text] [PDF]

				Yi Xu, V. Menon, and B. I Jugdutt Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-{varepsilon} in acutely reperfused myocardial infarction in the dog: Effect of UP269-6 and losartan on AT1- and AT2-receptor expression and IP3 receptor and PKC{varepsilon} proteins Journal of Renin-Angiotensin-Aldosterone System, June 1, 2000; 1(2): 184 - 195. [Abstract] [PDF]

				A. A. Bavry, D. Li, D. S. Zander, M. I. Phillips, and J. L. Mehta Inhibition of Arterial Thrombogenesis by Quinapril but Not Losartan Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(2): 121 - 127. [Abstract] [PDF]

				W. R. Ford, A. S. Clanachan, and B. I. Jugdutt Characterization of Cardioprotection Mediated by AT2 Receptor Antagonism After Ischemia-Reperfusion in Isolated Working Rat Hearts Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(3): 211 - 221. [Abstract] [PDF]

				B. I. Jugdutt, Yi Xu, M. Balghith, R. Moudgil, and V. Menon Cardioprotection Induced by AT1R Blockade After Reperfused Myocardial Infarction: Association With Regional Increase in AT2R, IP3R and PKC{varepsilon} Proteins and cGMP Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 2000; 5(4): 301 - 311. [Abstract] [PDF]

				K. L. Butler, A. H. Huang, and J. K. Gwathmey AT1-receptor blockade enhances ischemic preconditioning in hypertrophied rat myocardium Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2482 - H2487. [Abstract] [Full Text] [PDF]

				D. Y. Li, Y. C. Zhang, M. I. Philips, T. Sawamura, and J. L. Mehta Upregulation of Endothelial Receptor for Oxidized Low-Density Lipoprotein (LOX-1) in Cultured Human Coronary Artery Endothelial Cells by Angiotensin II Type 1 Receptor Activation Circ. Res., May 14, 1999; 84(9): 1043 - 1049. [Abstract] [Full Text] [PDF]

				D. Li, B. Yang, M. I. Philips, and J. L. Mehta Proapoptotic effects of ANG II in human coronary artery endothelial cells: role of AT1 receptor and PKC activation Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H786 - H792. [Abstract] [Full Text] [PDF]

				D. Li, K. Tomson, B. Yang, P. Mehta, B. P. Croker, and J. L. Mehta Modulation of constitutive nitric oxide synthase, bcl-2 and Fas expression in cultured human coronary endothelial cells exposed to anoxia-reoxygenation and angiotensin II: role of AT1 receptor activation Cardiovasc Res, January 1, 1999; 41(1): 109 - 115. [Abstract] [Full Text] [PDF]

				B. C. Yang, M. I. Phillips, Y. C. Zhang, B. Kimura, L. P. Shen, P. Mehta, and J. L. Mehta Critical Role of AT1 Receptor Expression After Ischemia/Reperfusion in Isolated Rat Hearts : Beneficial Effect of Antisense Oligodeoxynucleotides Directed at AT1 Receptor mRNA Circ. Res., September 7, 1998; 83(5): 552 - 559. [Abstract] [Full Text] [PDF]

				B. Yang, D. Li, M I. Phillips, P. Mehta, and J. L Mehta Myocardial angiotensin II receptor expression and ischemia-reperfusion injury Vascular Medicine, May 1, 1998; 3(2): 121 - 130. [Abstract] [PDF]

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